Extended release formulations of erythromycin derivatives

ABSTRACT

Disclosed is a pharmaceutical composition for extended release of an erythromycin derivative in the gastrointestinal environment. The composition comprises an erythromycin derivative and a pharmaceutically acceptable polymer so that, when ingested orally, the composition induces statistically significantly lower C max  in the plasma than an immediate release composition of the erythromycin derivative while maintaining bioavailability and minimum concentration substantially equivalent to that of the immediate release composition of the erythromycin derivative upon multiple dosing. The compositions of the invention have an improved taste profile and reduced gastrointestinal side effects as compared to those for the immediate release composition.

The present application is a continuation-in-part of U.S. patentapplication Ser. No. 08/838,900, filed Apr. 11, 1997, now allowed.

TECHNICAL FIELD

The present invention relates to pharmaceutical compositions oferythromycin derivatives with an extended release of an active compoundin the gastrointestinal environment. More particularly, it relates topharmaceutical compositions of clarithromycin which are ingested dailyas a single oral administration.

BACKGROUND OF THE INVENTION

Erythromycin and its derivatives are known for their antibacterialactivity against a number of organisms or activity in a number ofindications and are typically administered as immediate release (IR)compositions, two or three times a day, for a regimen of 10 to 14 days.These compounds have a bitter taste. In particular, the6-O-methoxyerythromycin A (clarithromycin) has a bitter metallic tastewhich can result in poor compliance of the regimen or selection ofanother, possibly less effective, therapeutic agent.

One approach to improve the possible non-compliance with the regimen hasbeen to develop controlled release solid preparations containing theseerythromycin derivatives in an alginate matrix comprising awater-soluble alginate and a complex salt of alginic acid, having onecation that yields a soluble alginate salt and another cation that aloneyields an insoluble alginate salt. These formulations are described inU.S. Pat. No. 4,842,866, issued Jun. 27, 1989. However, in-vivo animalstudies showed that reproducibly bioavailable controlled releaseformulation were not possible using alginates or any other monolithichydrogel tablets.

To overcome some of the problems associated with the formulationsdescribed in U.S. Pat. No. 4,842,866, improved controlled releaseformulations for poorly soluble basic drugs such as erythromycinderivatives including clarithromycin, have been developed and aredescribed in commonly owned, co-pending U.S. patent application Ser. No.08/574,877, filed Dec. 19, 1995. The formulations described in thepatent application comprise a poorly soluble basic drug and citric acidin an alginate matrix. The formulations are administered once a day andare directed towards increasing the bioavailability of the activeingredient so that it is bioequivalent with the current immediaterelease, twice-a-day compositions. However, these controlled releasecompositions do not purport to minimize the adverse effects related togastrointestinal (GI) disorders including nausea and vomiting and aphenomenon described as taste perversion.

One approach to address taste perversion has been to develop acceptablepalatable liquid oral dosage forms of these drugs as described in U.S.Pat. No. 4,808,411, issued Feb. 28, 1989. However, these formulationsare administered twice a day for a period of 10 to 14 days and do notaddress the frequency and duration of the administration regimen, or theadverse effects related to GI disorders. Therefore, there still exists aneed for developing a pharmaceutical composition which minimizes theadverse effects described above and provides a degree of drug plasmaconcentration control which is equivalent to or better than the (IR)tablet or liquid formulations currently used.

SUMMARY OF THE INVENTION

It has been discovered that the extended release (ER) formulations ofthe present invention which comprise a pharmaceutically acceptablepolymer, provide extended release clarithromycin in vivo when given oncedaily. Maximum concentrations (C_(max)) of clarithromycin in plasma arestatistically significantly lower than the IR formulation given twicedaily, and area under the plasma concentration-time curve (AUC) and theminimum plasma concentration are maintained over 24 hours. In contrast,for the controlled release formulations described in the co-pending U.S.application Ser. No. 08/574,877, filed Dec. 19, 1995, the C_(max) valuesare not statistically significantly different from those for the IRformulation. And while the AUC₀₋₂₄ is maintained, the C_(min) isstatistically significantly lower for the controlled-releaseformulations relative to the IR formulation. The compositions of theinvention have surprisingly a two-to three-fold reduction in incidencerates for taste perversion compared to the IR formulation.

In one aspect, the present invention relates to a pharmaceuticalcomposition for extended release of an erythromycin derivative in thegastrointestinal environment, comprising an erythromycin derivative anda pharmaceutically acceptable polymer, so that when ingested orally, thecomposition induces statistically significantly lower mean fluctuationindex in the plasma than an immediate release composition of theerythromycin derivative while maintaining bioavailability substantiallyequivalent to that of the immediate release composition of theerythromycin derivative.

In another aspect, the present invention relates to a pharmaceuticalcomposition for extended release of an erythromycin derivative in thegastrointestinal environment, comprising an erythromycin derivative anda pharmaceutically acceptable polymer, so that upon oral ingestion,maximum peak concentrations of the erythromycin derivative arestatistically significantly lower than those produced by an immediaterelease pharmaceutical composition, and an area under theconcentration-time curve and the minimum plasma concentration aresubstantially equivalent to that of the immediate release pharmaceuticalcomposition.

In yet still another aspect, the present invention relates to a methodof using an extended release, pharmaceutical composition comprising anerythromycin derivative and a pharmaceutically acceptable polymer,comprising administering the composition in an effective amount for thetreatment of bacterial infection in a mammal, whereby an area under theconcentration-time curve equivalent to that for an immediate releasepharmaceutical composition of the erythromycin derivative is maintained.

In yet another aspect, the present invention is an extended releasepharmaceutical composition comprising an erythromycin derivative and apharmaceutically acceptable polymer, wherein the composition has animproved taste profile relative to the immediate release formulation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the mean in vivo plasma concentration-time profilesfollowing single dose of three 500 mg ER tablets containingclarithromycin and 10%, 20% or 30%, respectively, by weight ofhydroxy-propylmethyl cellulose K 100 LV, as compared to that of thereference 500 mg IR clarithromycin tablet.

FIG. 2 illustrates the mean in vivo plasma concentration-time profilesfollowing multiple doses of each of the two ER tablets containing 10% or20%, respectively, of hydroxypropylmethyl cellulose K100 LV as comparedto the reference IR tablet. The dosage forms included two 500 mg ERtablets given once daily or one IR 500 mg clarithromycin every 12 hours,respectively, administered for three days with food.

FIG. 3 illustrates the mean in vivo plasma concentration-time profilesfollowing multiple doses of clarithromycin once-daily 1000 mg (not anexample of the invention) and IR 500 mg twice-a-day.

DETAILED DESCRIPTION OF THE INVENTION

“500 mg or 1000 mg” as used herein, means the strength of tabletcomposition containing 500 mg clarithromycin, or the dose administeredas 2×500 mg of clarithromycim, respectively.

“C_(max)” as used herein, means maximum plasma concentration of theerythromycin derivative, produced by the ingestion of the composition ofthe invention or the IR comparator.

“C_(min)” as used herein, means minimum plasma concentration of theerythromycin derivative, produced by the ingestion of the composition ofthe invention or the IR comparator.

“C_(avg)” as used herein, means the average concentration within the24-hour interval.

“T_(max)” as used herein, means time to the maximum observed plasmaconcentration

“AUC” as used herein, means area under the plasma concentration-timecurve, as calculated by the trapezoidal rule over the complete 24 hourinterval for all the formulations.

“Degree of Fluctuation (DFL)” as used herein, is expressed as:DFL=(C_(max)−C_(min))/C_(avg).

“Erythromycin derivative” as used herein, means erythromycin having nosubstituent groups, or having conventional substituent groups, inorganic synthesis, in place of a hydrogen atom of the hydroxy groupsand/or a methyl group of the 3′-dimethylamino group, which is preparedaccording to the conventional manner.

“Pharmaceutically acceptable” as used herein, means those compoundswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, in keeping with areasonable benefit/risk ratio, and effective for their intended use inthe chemotherapy and prophylaxis of antimicrobial infections.

“Adverse effects” as used herein, means those physiological effects tovarious systems in the body such as cardiovascular systems, nervoussystem, digestive system, and body as a whole, which cause pain anddiscomfort to the individual subject.

“Taste perversion” as used herein, means the perception of a bittermetallic taste normally associated with the erythromycin derivatives,particularly, with clarithromycin.

The pharmaceutical composition of the invention comprise apharmaceutically active compound and a pharmaceutically acceptablepolymer. The pharmaceutically active compound is an erythromycinderivative. Preferably, the erythromycin derivative is 6-O-methoxy,erythromycin A, known as clarithromycin. The amount of the erythromycinderivative varies from about 45% to about 60% by weight of thecomposition. Preferably, the composition comprises about 50% by weightof the erythromycin derivative.

The pharmaceutically acceptable polymer is a water-soluble hydrophilicpolymer selected from the group consisting of polyvinylpyrrolidine,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, vinyl acetate/crotonic acid copolymers, methacrylic acidcopolymers, maleic anhydride/methyl vinyl ether copolymers andderivatives and mixtures thereof. Preferably, the polymer is selectedfrom hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and methylcellulose. More preferably, the polymer is hydroxypropylmethylcellulose. Most preferably, the polymer is a low viscosityhydroxypropyl-methyl cellulose with viscosity ranging from about 50 cpsto about 200 cps. The most preferred low viscosity polymer is ahydroxypropylmethyl cellulose with a viscosity of about 100 cps,commercially available under the Tradename Methocel™ K 100 LV from TheDow Chemical Company.

The amount of the polymer in the composition generally varies from about5% to about 50% by weight of the composition. Preferably, the amount ofpolymers varies from about 10% to about 35% by weight of thecomposition. Most preferably, the amount of polymer varies from about10% to about 30% by weight of the polymer.

The composition of the invention further comprise pharmaceuticallyacceptable excipients and/or fillers and extenders, such as lactose,starches, glucose, sucrose, mannitol, and silicic acid, lubricants suchas talc, calcium stearate, magnesium stearate, solid polyethyleneglycols, sodium lauryl sulfate, and mixtures thereof.

The amount of the lubricants generally varies from about 0.5% to about10% by weight of the composition. Preferably, the lubricants used aremagnesium stearate and talc in the total amounts ranging from about 1.0%to about 4.0% by weight of the composition. The amount of fillers andextenders varies from about 10% to about 40% by weight of thecomposition.

A particularly preferred composition for the extended release of theactive compound therefrom comprises:

-   -   about 500 mg of clarithromycin; and    -   from 100 to 300 mg of Methocel K 100 LV.

The formulations are generally prepared by dry blending the polymer,filler, erythromycin derivative, and other excipients followed bygranulating the mixture using water until proper granulation isobtained. The granulation is done by methods known in the art. The wetgranules are dried in a fluid bed dryer, sifted and ground toappropriate size. Lubricating agents are mixed with the driedgranulation to obtain the final formulation.

The compositions of the invention can be administered orally in the formof tablets, pills, or suspensions. The tablets can be prepared bytechniques known in the art and contain a therapeutically useful amountof erythromycin derivative and such excipients as are necessary to formthe tablet by such techniques. Tablets and pills can additionally beprepared with enteric coatings and other release-controlling coatingsfor the purpose of light protection, and swallowability. The coating maybe colored with a pharmaceutically accepted dye. The amount of dye andother excipients in the coating liquid may vary and will not impact theperformance of the extended release tablets. The coating liquidgenerally comprises film-forming polymers such as hydroxy-propylcellulose, hydroxypropylmethyl cellulose, cellulose ester or ether, anacrylic polymer or a mixture of polymers. The coating solution isgenerally an aqueous solution further comprising propylene glycol,sorbitan monoleate, sorbic acid, fillers such as titanium dioxide, apharmaceutically acceptable dye.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs containing inert diluents commonly used in the art such aswater. Such compositions may also comprise adjuvants, such as wettingagents; emulsifying and suspending agents; and sweetening, flavoring andperfuming agents.

The daily dose of the composition of this invention administered to ahost in single dose can be in the amounts from 500 mg to 1000 mg once aday for five to fourteen days.

Pharmacokinetic Study

The bioavailability study for the formulations of the invention can bedone by administering the ER formulation in a tablet form to healthysubjects and measuring the levels of erythromycin derivative in theplasma at different time intervals over a period of twenty four hours,

Plasma samples are assayed for erythromycin derivative at BAS Analytics(West Lafayette, Ind.) using a validated high-performance liquidchromatographic procedure similar to that described in the literature.See for example, Chu S-Y, et al., “Simultaneous determination ofclaritdromycin and 14(R)-hydroxyclarithromycin in plasma and urine usinghigh-performance liquid chromatography with electrochemical detection”,J. Chromatog., 571, pp 199-208 (1991).

Adverse Effects and Taste Profile

Adverse effects including those related to the digestive system, nervoussystem, respiratory system and special senses, including tasteperversion, are measured by dosing subjects with multiple doses of 1000mg of ER and IR tablets per day, respectively. The adverse effects aremonitored, reported spontaneously by subjects and recorded on casereport forms for the study database.

The invention will be understood more clearly from the followingExamples, which are given solely by way of illustration and serve toprovide a clear understanding of the invention and to illustrate itsdifferent embodiments as well as its various advantages.

EXAMPLES Example 1 Preparation of Formulation

Methocel™ (K 100 LV) available from The Dow Chemical Company was loadedinto a mixer, and dry blended with clarithromycin. The mixture wasgranulated using water until proper granulation was obtained. Thegranulation was then dried, sifted and ground to appropriate size.

Talc and magnesium stearate were screened and blended with drygranulation. The granulation was then loaded into hopper and compressedinto tablets. The tablets were then coated with an aqueous coating.

Three different formulations A, B, and C were prepared according to thegeneral method described above. The compositions of three differenttablet formulations are given below in Table 1. TABLE 1 A B C Ingredientmg/tablet mg/tablet mg/tablet Water (USP, purified) Q.S. Q.S. Q.S.Clarithromycin 500.00 500.00 500.00 Methocel K 100 LV Premium CR 200.00100.00 300.00 Grade* Lactose, monohydrate 260.00 360.00 160.00 Talc, USP30.00 30.00 30.00 Magnesium Stearate 10.00 10.00 10.00*Available from The Dow Chemical Company

Example 2 Pharmacokinetic Study of the Extended Release Formulation

The bioavailability study to determine the concentration-time plasmaprofile was done on healthy subjects. The study was conducted as a PhaseI, single-dose, open, randomized, four-period, balanced crossover studydescribed below.

Single-Dose Study

Twenty-four (24) healthy adult subjects were enrolled and 23 completedall phases of the study. For the 23 subjects who completed all phases ofthe study (12 males, 11 females), the mean age was 29 years (range: 19to 49 years), the mean weight was 69.0 kg (range: 51.5 to 85 kg) and themean height was 172 cm (range: 157 to 192 cm).

Clarithromycin 500 mg extended release tablets corresponding to theformulations A, B, and C of Example 1 and the 500 mg IR clarithromycintablet (Reference Formulation), currently sold by Abbott Laboratoriesunder the Tradename BIAXIN™, were administered to the 23 healthysubjects.

The study was conducted according to a single-dose, open-label,randomized four-period crossover design in which each subject received asingle 500 mg dose of clarithromycin during each 30 minutes period afterstarting breakfast. Wash-out periods of one week separated the doses.

Seven (7) ml blood samples were collected prior to dosing (0 hour) andat 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 24.0, 36.0 and 48.0hour after each dose. Plasma samples were assayed for clarithromycin atBAS Analytics (West Lafayette, Ind.) using a validated high performanceliquid chromatographic procedure.

Pharmacokinetic Analyses

Values for clarithromycin pharmacokinetic parameters, including observedC_(max), T_(max), and AUC₀₋∞, were calculated using standardnoncompartmental methods.

The mean plasma concentration-time profiles for the single-dose studyare illustrated in FIG. 1.

FIG. 1 illustrates that all the three formulations of the invention aresubstantially equivalent in extended release of clarithromycin over aperiod of 24 hours.

Table II summarizes the pharmacokinetic results obtained aftersingle-dosing in the above study. TABLE II AUC_(0-∞) Formulation C_(max)(μg/ml) T_(max) (h) (μg · h/mL A 1.19 ± 0.60* 5.0 ± 1.7* 15.0 ± 6.5* B 1.33 ± 0.70*# 5.5 ± 2.4* 15.1 ± 6.5* C 1.01 ± 0.48* 5.5 ± 2.2* 14.8 ±7.5* Reference Tablet 2.57 ± 0.70  2.2 ± 0.5  17.7 ± 5.6 *Statistically significantly different from the IR reference tablet#Statistically significantly different from Formulations A and C inanalysis of logarithmsStatistical Analyses

For C_(max), AUC₀₋∞, T_(max), and the logarithms of C_(max), and AUC₀₋∞,an analysis of variance (ANOVA) was performed with sequence, subjectnested within sequence, period and formulation as the sources ofvariation. Effects for subjects were random and all other effects werefixed. Within the framework of ANOVA, the formulations were comparedpairwise, with each test at a significance level of 0.05 Also within theframework of the ANOVA for the logarithm of AUC₀₋∞, bioequivalence ofthe ER formulations to the IR reference formulation was assessed usingthe two one-sided tests procedure via 90% confidence intervals. Theconfidence intervals were obtained by exponetiating the endpoints of theconfidence intervals for the difference of logarithm means.

Point estimates of relative bioavailability and 90% confidence intervalsfor the two one-sided tests procedure from analysis of log-transformedAUC₀₋∞ are set forth in Table III below. TABLE III RelativeBioavailability Formulation Comparison Point Estimate 90% ConfidenceInterval A vs Reference 0.815 0.737-0.902 B vs Reference 0.8350.755-0.925 C vs Reference 0.787 0.711-0.871

The AUC₀₋∞ central values were lower for the three ER formulations thanfor the reference IR tablet. The lower C_(max) values and the laterT_(max) values suggest that all the ER formulations with varying weightpercent of polymer, provide extended-release of clarithromycin in vivo.

The lower AUC₀₋∞ values for the ER formulations may suggest that for asingle 500 mg dose administered under nonfasting conditions, the extentof absorption of clarithromycin was reduced relative to that of thereference IR tablet.

Multiple-Dose Study

Twenty-four (24) healthy adult subjects were enrolled and 23 completedall phases of the study. Of the 23 who completed the study (19 males, 4females), the mean age was 30 years (range: 20 to 47 years), the meanweight was 72 kg (range: 51 to 87 kg) and the mean height was 176 cm(range: 159 to 189.5 cm).

The clarithromycin dosage forms included 500 mg ER tablets of Example 1containing 10% or 20% by weight of K 100 LV, respectively, and areference 500 mg IR tablet (BIAXIN).

The study was conducted according to a single- and multiple-dose,open-label, randomized three-period crossover design.

Regimen A

A single 1000 mg dose of ER formulation A tablets (two 500 mg tablets)was administered in the morning on Day 1. Beginning on Day 3, a multipledose regimen of 1000 mg clarithromycin (two 500 mg tablets) wasadministered each morning for three days (Days 3-5).

Regimen B

A single 1000 mg dose of ER formulation B tablets (two 500 mg tablets)was administered in the morning on Day 1. Beginning on Day 3, a multipledose regimen of 1000 mg clarithromycin (two 500 mg tablets) wasadministered each morning for three days (Days 3-5).

Regimen C

A single 500 mg dose of IR tablet (BIAXIN) was administered in themorning on Day 1. Beginning on Day 3, a multiple dose regimen of 500 mgreference tablet BIAXIN was administered every twelve hours for threedays.

Each morning dose was administered thirty minutes after breakfast. Everyevening dose was administered thirty minutes after starting the eveningsnack.

Wash-out periods of at least one week separated the last dose in aperiod and the first dose in the following period.

Seven (7) ml blood samples were collected before dosing on Day 1 (0 hr)and at 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 24.0, 36.0, and48.0 hour after dosing. For Regimen C, the 12 hour sample was collectedwithin 5 minutes before the evening dose on Day 5. Plasma-harvested fromeach blood sample was divided into two parts: approximately 5 mL forbioassay and the remainder of the sample for high performance liquidchromatographic (HPLC) assay. Plasma samples were assayed forclarithromycin at BAS Analytics (West Lafayette, Ind.) using a validatedhigh performance liquid chromatographic procedure.

Pharmacokinetic Analyses

Pharmacokinetic parameter estimates were calculated usingnoncompartmental methods. For the Day 1 data, the parameters estimatedincluded C_(max), T_(max), AUC₀₋∞ or AUC₀₋₄₈, and t_(1/2). For the Day 5data, the parameters estimated included C_(max), T_(max), C_(min),AUC₀₋₂₄, and DFL.

Statistical Analyses

No statistical analyses were performed on the bioassay data. Analyses ofvariance (ANOVA) were performed for Day 1 and Day 5 pharmacokineticvariables with effects for regimen, period, sequence, and subject nestedwithin sequence. The C_(max) and AUC₀₋ values for Regimen C werenormalized to a 1000 mg dose. For the Day 1 and Day 5 AUC and C_(max)values and for the Day 5 DFL values for both analytes, logarithmictransformation was employed. Each of the Regimens A and B were comparedto the reference Regimen C at a significance level of 0.05. Within theframework of the ANOVAs for the Day 5 AUC values, equivalence of the ERformulations of the invention to the IR reference tablet was assessedusing the two one-sided tests procedure via 90% confidence intervals.

The mean plasma concentration-time profiles for the multiple-dose studyare illustrated in FIG. 2.

Table IV summarizes (mean±SD) of the Day 5 pharmacokinetic parameterestimates for the clarithromycin in the ER and IR formulations. TABLE IVC_(max) C_(min) T_(max) AUC₀₋₂₄ Fluctuation Formulation (μg/ml) (μg/ml)(h) (μg · h/mL0 Index A 2.45 ± 0.69* 0.70 ± 0.37 8.6 ± 4.4* 39.6 ± 12.81.11 ± 0.31*† B 2.66 ± 0.87* 0.67 ± 0.39 6.9 ± 3.3* 40.2 ± 13.8 1.24 ±0.37* IR 3.21 ± 0.78 0.78 ± 0.29 1.9 ± 0.6 40.8 ± 11.8 1.47 ± 0.26Reference*Statistically significantly different from the reference IRformulation.†Statistically significantly different from Regimen B.

Point estimates of the relative bioavailability and 90% confidenceintervals for the two one-sided tests procedures of Day 5 AUC₀₋₂₄ areset forth in Table V below. The results presented are forlogarithmic-transformed clarithromycin AUC₀₋₂₄ values. TABLE V RelativeBioavailability Formulation Comparison Point Estimate 90% ConfidenceInterval A vs Reference 0.964 0.893-1.039 B vs Reference 0.9700.899-1.046

For this multiple dose study under nonfasting conditions, both the 10%and 20% polymer ER formulations were bioequivalent to the reference IRtablet with respect to the AUC₀₋₂₄. The significantly lower C_(max)central values and later T_(max) values suggest that both theformulations provide extended release of clarithromycin in vivo. Thesignificantly lower DFLs indicate that plasma concentrations fluctuateless for the ER tablet regimens than for the IR tablet regimen.Additionally, the significantly lower DFL for Regimen A compared toRegimen B indicates that plasma concentrations from the 20% polymerfluctuate less than those from the 10% polymer tablet.

Adverse Effects

The adverse effects, including taste perversion (taste profile), werestudied for the multiple-dose regimes described above.

Multiple-Dose Study

The formulations A and B of Example 1 (500 mg tablets) and the IR BIAXIN(reference) 500 mg tablet were administered to healthy subjects in amultiple-dose regimen as described above.

Formulations of the Invention

A single dose (2×500 mg) of the formulations A and B of Example 1, wasadministered to the subjects, followed by a 48 hour wash-out period.Multiple dosing in the morning with the 2×500 mg regimen, once-a-day,followed the washout for the next three days.

Reference

A single dose of 500 mg IR BIAXIN tablet was administered to thesubjects, followed by a 48 hour wash-out period. Multiple dosing withthe 500 mg tablet, twice-a-day followed the washout for three days.

The adverse effects to the body as a whole, cardiovascular system,digestive system, nervous system, respiratory system, skin andappendages, and special senses were measured by monitoring the subjectsat regular time intervals. Subjects who reported the same COSTART termmore than once were counted only once for that COSTART term.

The results of the adverse effects are set forth in Table VI below.TABLE VI DOSING REGIMEN A B Reference BODY SYSTEM (N_(m) 24) (N_(m) 23)(N_(m) 23) COSTART TERM Percent of Total Subjects Overall  9 (37.5%) 10(43.5%) 11 (47.8%) Body As A Whole  6 (25.0%)  3 (13.0%) 1 (4.3%)Asthenia 2 (8.3%) 1 (4.3%) 0 (0.0%) Chills 0 (0.0%) 1 (4.3%) 0 (0.0%)Headache 2 (8.3%) 2 (8.7%) 0 (0.0%) Neck Rigidity 1 (4.2%) 0 (0.0%) 0(0.0%) Pain 2 (8.3%) 0 (0.0%) 1 (4.3%) Cardiovascular System 1 (4.2%) 0(0.0%) 0 (0.0%) Hypertension 1 (4.2%) 0 (0.0%) 0 (0.0%) Digestive System 4 (16.7%)  4 (17.4%)  4 (17.4%) Abdominal Pain 1 (4.2%) 0 (0.0%) 0(0.0%) Constipation 0 (0.0%) 0 (0.0%) 2 (8.7%) Diarrhea 2 (8.3%)  3(13.0%) 1 (4.3%) Dyspepsia 2 (8.3%) 2 (8.7%) 1 (4.3%) Flatulence 0(0.0%) 1 (4.3%) 0 (0.0%) Nausea 0 (0.0%) 0 (0.0%) 1 (4.3%) NervousSystem 0 (0.0%) 1 (4.3%) 2 (8.7%) Depersonalization 0 (0.0%) 1 (4.3%) 0(0.0%) Hypesthesia 0 (0.0%) 1 (4.3%) 1 (4.3%) Insomnia 0 (0.0%) 1 (4.3%)0 (0.0%) Somnolence 0 (0.0%) 0 (0.0%) 1 (4.3%) Respiratory System 1(4.2%) 1 (4.3%)  3 (13.0%) Cough Increased 1 (4.2%) 0 (0.0%) 0 (0.0%)Hiccup 0 (0.0%) 0 (0.0%) 1 (4.3%) Pharyngitis 0 (0.0%) 1 (4.3%) 2 (8.7%)Rhinitis 1 (4.2%) 1 (4.3%) 0 (0.0%) Skin and Appendages 0 (0.0%) 2(8.7%) 2 (8.7%) Rash 0 (0.0%) 1 (4.3%) 1 (4.3%) Skin Disorder 0 (0.0%) 1(4.3%) 2 (8.7%) Special Senses  3 (12.5%)  3 (13.0%)  6 (26.1%) EyeDisorder 0 (0.0%) 1 (4.3%) 0 (0.0%) Taste Perversion  3 (12.5%) 2 (8.7%) 6 (26.1%)

It is evident from the above Table VI that the adverse effects to thedigestive, nervous and respiratory systems normally associated withBIAXIN are reduced with the ER tablets. The taste perversion with theformulations of the invention is significantly reduced. It is reasonablybelieved that the reduced adverse effects, particularly tasteperversion, would lead to better compliance and a higher incidence ofcompletion of the prescribed treatment regimen.

Comparative Example 3

The results of a comparative pharmacokinetic study of the controlledrelease formulation A of the co-owned, pending U.S. patent applicationSer. No. 08/574,877, filed Dec. 19, 1995, as compared with the IR(BIAXIN) are set forth in Table VII below. TABLE VII Clarithromycin 1000mg Clarithromycin Once-Daily 500 mg BID (Formulation Reference 90%PK-Parameter A) (BIAXIN) Point Confidence Unit Mean^(a) S.D.^(b)Mean^(a) S.D.^(b) Estimator^(c) Interval AUC₀₋₂₄ (μg * h/ml) 27.29810.086 28.256 10.770 97.4 86.9-109.2 C_(max) (μg/ml) 2.432 0.905 2.7010.785 89.0 78.2-101.3 T_(max) (h) 5.217 1.858 2.043 0.706 C_(min)(μg/ml) 0.469 0.292 0.597 0.241 71.7 60.0-85.7  DFL 1.800 0.572 1.9000.616^(a)arithmetic means^(b)standard deviation^(c)defined as the ratio of the geometric means of test vs. referenceformulation

The mean DFL for the composition of the invention is statistically lowerthan the IR in vivo profile. The lower DFL indicates that the ERformulations of the invention provide less variable clarithromycinconcentrations throughout the day than the IR and the sustained releasecompositions.

The mean DFL values for the controlled release formulation and for theIR are substantially equal in value as can be seen in the above Table.cf. 1.800±0.572 (for controlled release) with 1.900±0.616, (IR).

Study of Gastrointestinal Adverse Effects in Patients

Two well-controlled, double-blind clinical trials were conducted tocompare the safety and efficacy of extended-release clarithromycin (ER)and immediate-release clarithromycin (IR) in patients with acutemaxillary sinusitis (AMS) and patients with acute bacterial exacerbationof chronic bronchitis (AECB).

A total of 910 patients were enrolled for the studies. Of the 910patients, 459 patients were treated with ER formulation of the inventionand 444 patients were treated with the IR (Reference) formulation.

Treatment

Two hundred eighty three (283) patients, enrolled in the AMS study, and627 patients, enrolled in the AECB study, were randomly assigned in a1:1 ratio to receive either the ER formulation of the invention or theIR formulation.

AMS Study

Of the 283 patients enrolled in this study, 142 patients received asingle dose of clarithromycin ER tablets 500 mg×2 QD (1000 mg daily) for14 days, and 141 patients received clarithromycin IR tablets, 500 mg BID(1000 mg daily) for 14 days.

AECB Study

Of the 627 patients enrolled in this study, 317 patients received asingle dose of clarithromycin ER tablets 500 mg×2 QD (1000 mg daily) for7 days, and 303 patients received clarithromycin IR tablets, 500 mg BID(1000 mg daily) for 7 days.

The results of the study are summarized below in Table VIII. TABLE VIIIClarithromycin ER Reference 1000 mg. once-daily BIAXIN Number ofpatients 0.6% 3.0%* discontinued due to drug- (3/459) (13/444) relatedGI adverse events Number of patients with severe 0.2% 2.0%* drug-relatedGI adverse events 1/459  (8/444)*Statistically significant p 0.05 level.

From the above results, it can be seen that patients taking theextended-release formulation of clarithromycin were significantly lesslikely to stop taking clarithromycin due to gastrointestinal adverseevents and these patients suffered significantly fewer severegastrointestinal adverse effects.

1-20. (canceled)
 21. A method of reducing gastrointestinal adverseevents associated with clarithromycin therapy comprising: administeringan extended release composition comprising clarithromycin wherein uponadministration, the composition provides a) a lower mean C_(max) thanthe immediate release composition having an equal amount ofclarithromycin, and b) a lower mean C_(max) than the controlled releaseformulation having an equal amount of clarithromycin, a water solublealginate salt, a complex salt of alginic acid and an organic carboxylicacid.
 22. A method of reducing gastrointestinal adverse eventsassociated with clarithromycin therapy comprising: administering anextended release composition comprising clarithromycin wherein uponadministration, the composition provides a) a lower mean degree offlucuation than the immediate release composition having an equal amountof clarithromycin, and b) a lower mean degree of fluctuation than thecontrolled release formulation having an equal amount of clarithromycin,a water soluble alginate salt, a complex salt of alginic acid and anorganic carboxylic acid.
 23. A method of reducing taste perversionassociated with clarithromycin therapy comprising: administering anextended release composition comprising clarithromycin wherein uponadministration, the composition provides a) a lower mean C_(max) thanthe immediate release composition having an equal amount ofclarithromycin, and b) a lower mean C_(max) than the controlled releaseformulation having an equal amount of clarithromycin, a water solublealginate salt, a complex salt of alginic acid and an organic carboxylicacid.
 24. A method of reducing taste perversion associated withclarithromycin therapy comprising: administering an extended releasecomposition comprising clarithromycin wherein upon administration, thecomposition provides a) a lower mean degree of flucuation than theimmediate release composition having an equal amount of clarithromycin,and b) a lower mean degree of fluctuation than the controlled releaseformulation having an equal amount of clarithromycin, a water solublealginate salt, a complex salt of alginic acid and an organic carboxylicacid.
 25. A method of increasing compliance with clarithromycin therapycomprising: providing a pharmaceutical composition for extended releaseof clarithromycin having a) a lower mean C_(max) than the immediaterelease composition having an equal amount of clarithromycin, and b) alower mean C_(max) than the controlled release formulation having anequal amount of clarithromycin, a water soluble alginate salt, a complexsalt of alginic acid and an organic carboxylic acid.
 26. A method ofincreasing compliance with clarithromycin therapy comprising: providinga pharmaceutical composition for extended release of clarithromycinhaving a) a lower mean degree of flucuation than the immediate releasecomposition having an equal amount of clarithromycin, and b) a lowermean degree of fluctuation than the controlled release formulationhaving an equal amount of clarithromycin, a water soluble alginate salt,a complex salt of alginic acid and an organic carboxylic acid.
 27. Amethod of increasing incidence of completion of a prescribed antibiotictherapy comprising providing a pharmaceutical compositon for extendedrelease of clarithromycin having a) a lower mean C_(max) than theimmediate release composition having an equal amount of clarithromycin,and b) a lower mean C_(max) than the controlled release formulationhaving an equal amount of clarithromycin, a water soluble alginate salt,a complex salt of alginic acid and an organic carboxylic acid.
 28. Amethod of increasing incidence of completion of a prescribed antiobiotictherapy comprising providing a pharmaceutical compositon for extendedrelease of clarithromycin having a) a lower mean degree of flucuationthan the immediate release composition having an equal amount ofclarithromycin, and b) a lower mean degree of fluctuation than thecontrolled release formulation having an equal amount of clarithromycin,a water soluble alginate salt, a complex salt of alginic acid and anorganic carboxylic acid.